Risk assessment validation in patients with pulmonary arterial hypertension: Data from a Southern Brazil registry (RESPHIRAR study)

Abstract Pulmonary arterial hypertension (PAH) is a severe and progressive disease characterized by increased pulmonary vascular resistance, ultimately leading to right heart failure and death. Registries are a valuable tool in the research of rare conditions such as PAH. Moreover, the risk assessment strategy has been validated in European and North American registries and has been reported to provide an accurate prediction of mortality and the clinical advantage of reaching low‐risk status. However, there is no available data from Brazil. Thus, the aim of the present study was to describe the characteristics of a sample of PAH from Southern Brazil and to retrospectively validate the risk assessment at our population. The RESPHIRAR is a retrospective and multicentric registry on pulmonary hypertension. With a join collaboration from nine centers in Southern Brazil, demographics, clinical presentation, and hemodynamics data of PAH were collected between 2007 and 2017. Moreover, the REVEAL 2.0 and REVEAL 2.0 Lite risk assessments were validated in our population. Overall, 370 PAH patients were included in the present study. Patients were predominantly female (78.5%) and had a mean age of 41.8 ± 18.8 years. Most patients (33.4%) had idiopathic PAH, 30.2% had PAH associated with congenital heart disease, and 23.5% had PAH associated with connective tissue disease. The low‐risk group showed significantly lower mortality than the intermediated‐ or high‐risk group at diagnosis (p < 0.05). In conclusion, our data suggest that REVEAL 2.0 and REVEAL 2.0 Lite risk assessments can predict mortality risk in PAH patients in Southern Brazil.


INTRODUCTION
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular obliteration and remodeling that leads to progressive right heart failure and death. 1,2 Last decades have witnessed significant improvements in knowledge about pathophysiology, epidemiology, prognostic factors, and treatment management; yet PAH remains a relentlessly progressive disease with unacceptable mortality. 3 Most of the current epidemiological data derive from national European and US registries 4,5 ; these registries allowed not only a better understanding of the clinical aspects of the disease but also the development of risk stratification tools that nowadays represent the mainstem of PAH management. [6][7][8][9][10][11][12] In the current PAH treatment guidelines, treatment is tailored according to the risk of disease progression and death. 13 A combination of different risk variables defines well validated low-, intermediate,-and high-risk groups. [14][15][16][17] According to the risk classification stratum treatment is initiated from double oral combination therapy, for the low risk profile, to combination therapy including parenteral prostanoids, for the high risk patients, with the goal of keeping/bringing the patient to a low risk of progression. [18][19][20] In this context, several risk scores are available to guide clinicians in determining prognosis for their patients with PAH, including The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), 2,14,21 REVEAL 2.0, 6,22 Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), 23,24 Swedish PAH Registry (SPAHR), 15,25 and French Pulmonary Hypertension Network (FPHN). 9 Generally, all have comparable efficacy in stratifying patients into low (<5%), intermediated (5%−10%), and high-risk (>10%) of mortality at 1 year. 26 Nevertheless, PAH patients from developing regions seem to have a slightly different clinical profile, [27][28][29] raising the question about the potential bias on directly extrapolating these risk stratification strategies to these regions. Thus, the aim of the present study was to validate the risk assessment in a large cohort from Southern Brazil.

The Southern Brazil PAH register
This was a multicentric retrospective cohort of prevalent cases, enrolling patients from nine pulmonary hypertension (PH) centers in Southern Brazil, including reference centers in the States of Rio Grande do Sul, Santa Catarina, and Paraná. The Registry of patients with Pulmonary Hypertension in Southern Brazil (RESPHIRAR) was created in January 2018 and was designed and fulfilled following Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. 30,31 A systematic data collection including baseline information of all consecutive PH patients diagnosed between 2007 and 2017 was performed. Date of the confirmatory right heart catheterization (RHC) was considered the date of diagnosis. 1 PH was classified following the World Health Organization (WHO) guidelines. 32 In RESPHIRAR registry, patients were eligible for enrollment if they met diagnostic criteria of PAH (group 1) or chronic thromboembolic pulmonary hypertension (CTEPH, group 4) according to international guidelines. 27 Additionally, based on the etiology of PAH, patients were divided into subgroups. Recorded data included demographic characteristics, clinical and laboratorial parameters, WHO Functional Class (FC), hemodynamics, therapy usage, and survival status. The present study followed the ethical principles for medical research in humans from the Helsinki Declaration. The study protocol was registered at ensaiosclinicos.gov.br under the number RBR-4fhbrp.

Risk assessment
The REVEAL Lite 2.0 and the REVEAL 2.0 were calculated to provide a simplified method of mortality risk assessment for adult patients with PAH. 6,22 For the REVEAL Lite 2.0 assessment (with score ranging from 1 to 14), a score between 1 and 5 was considered low risk, a score of 6 or 7 was considered intermediated risk, and a score of 8 or higher was considered high risk. 22 For the REVEAL 2.0 assessment (with scores ranging from 0 to 23), a score between 0 and 6 was considered low risk, a score of 7 or 8 was consider intermediate risk, and a score of 9 or higher was considered high risk. 6

Statistical analysis
Normal distribution of data was assessed using Kolmogorov−Smirnov test. Variables with normal distribution are presented as mean ± standard deviation. Variables with skewed distribution were logtransformed before analysis and are presented as median (25th-75th percentiles). Categorical data are shown as percentages. One-way ANOVA followed by Tukey post hoc tests was used to compare the continuous variables distribution among the three PAH subgroups. Values with significant differences were indicated by different superscript letters (p < 0.05), while statistically similar values were indicated by the same superscript letters. χ 2 test was used for categorical variables.
Survival analysis was performed using the Kaplan− Meier method, with the date of entry into the study defined as the date of the first diagnostic RHC. All-cause mortality was defined as the endpoint and the log-rank test was used for comparison between groups. Of note, Kaplan−Meier curves are absolute survival. None of the patients included in RESPHIRAR cohort underwent lung transplantation or atrial septostomy. The latter were censored at the time of their last evaluations. p < 0.05 were considered statistically significant. Statistical analyses were performed using the SPSS statistical package (v.28.0) for Windows (SPSS Inc.).

RESPHIRAR registry
The RESPHIRAR registry retrieved data from 602 PH prevalent patients. Of these, 67 patients had to be excluded because they were diagnosed with PH groups 2, 3, or 5. Additionally, another four patients were excluded because of missing data. Moreover, 61 were children or adolescents. A total of 470 adult patients were enrolled in the RESPHIRAR registry: most of them were female (77.3%), white (89.9%), and with a mean age of 48.3 ± 7.1 years. Among these 470 patients, 370 (78.7%) had PAH and were analyzed in great depth in the present article. Patient selection flowchart are shown in Supporting Information: Figure 1.

PAH adult population description
Demographic, hemodynamic, and clinical characteristics at PAH diagnosis are presented in Table 1. Among of these patients, most of them female (78.5%), with mean age of 41.8 ± 18.8 years. Most of patients were in WHO FC II or III at diagnosis (80.2%). Most common treatment consisted of monotherapy in 72.3% of PAH patients, followed by double combination therapy in 26.3% and triple combination in 1.4%. The majority started with phosphodiesterase-5 inhibitors (PDE5i) or endothelinreceptor antagonist. At diagnosis, the most common presenting symptom was dyspnea (87.9%), followed by fatigue (78.1%) (Figure 1a). Moreover, at baseline, the most frequent comorbidity is system arterial hypertension (27%), followed by thyroid dysfunction, obesity, and diabetes mellitus (Figure 1b).
The distribution and characteristics of patients with idiopathic PAH, PAH-CHD, or PAH-CTD are shown in Table 1. The three groups are different in age. As expected, patients with PAH-CHD were younger and presented lower BMI levels compared to idiopathic and PAH-CTD subgroups, while patients with PAH-CTD were older than the other two groups. The prevalence of women was higher in PAH-CTD group compared to the other two groups. Although the significance did not reach formal statistical levels, PAH-CTD patients walked less than the other two groups (p > 0.05). Considering hemodynamic data, the three subgroups differ in terms of systolic and diastolic PAP and mPAP measurements (p < 0.001).

Risk assessment at time of PAH diagnosis
At baseline, the mean REVEAL Lite 2.0 risk score was 6.3 ± 1.6 for PAH patients. Most patients (49.7%) were in the intermediate-risk stratum at baseline, 28.1% were in the low-risk stratum, and 22.2% were in the high-risk stratum. After 5-years of follow-up, survival of patients at low-risk at baseline was 84.7%, at intermediate-risk was 78.4%, and at high-risk was 67.5% (Log-rank p = 0.021, Figure 3a). In the same way, implementing the REVEAL 2.0 risk score the similar results were found: 41.7% of patients were in the intermediate-risk stratum at baseline, 37.4% were in the low-risk stratum, and 20.9% were in the high-risk stratum. After 5-years of follow-up, survival of patients at low-risk at baseline was 81.7%, at intermediate-risk was 76.4%, and at high-risk was 60.5% (Log-rank p = 0.034, Figure 3b). Interestingly, when comparing low risk to intermediate + high-risk, the REVEAL 2.0, this stratification score was able to differentiate the two groups regarding the survival of patients at 5-years of follow-up (p = 0.034). For both stratifications risk scores, there is no difference among PAH subgroups (p > 0.05).

DISCUSSION
In the present study, we retrospectively validated the REVEAL 2.0 and REVEAL Lite 2.0 also for developing regions, with specific patients' characteristics. Using these two-risk assessment, we demonstrated that patients in the low-risk group at baseline had significantly low mortality than those in the intermediate-and high-risk groups in a cohort of PAH patients from Southern Brazil.
Generally, patients with PAH in our registry were comparable to those in other registries in terms of WHO FC distribution, female-to-male ratio, main hemodynamics parameters, and symptoms at diagnosis. However, the most interestingly finding is that the mean 6 min walking distance (6MWD) in participants of our cohort was higher compared to several registries. 1,27,33,34 This result agrees with previous data other Brazilian cohorts that has also suggested that the 6MWD is higher than the one found in United States and Europe. 1,7 One of possible explanations for these findings is that the mean age of patients was lower in Brazil, which could contribute to a better 6MWD. 27,28 Although registries from US and Europe had described an increasing proportion of older patients diagnosed with idiopathic PAH, in developing countries, the average age of patients with idiopathic PAH is younger than 40 years, [27][28][29]35 which corroborate with the RESPHIRAR registry findings. These differences may be explained by several factors, including overall population age distribution between developed and developing countries (older population in Europe and United States) and healthcare systems. 35,36 However, other factors may play a role such as: referral patterns, PAH awareness, increase patient access to information, and widespread use of noninvasive screening tools. 1 Corroborating with this result, the percentage of CHD-PAH patients in our population was also higher compared to the frequency described in most registries, especially the ones from European population. 33,37,38 It is known that developing countries have a greater number of patients with uncorrected or late correction congenital heart disease in childhood. Thus, it is vitally important to have a global view of PAH, as registries in developing countries may be exhibit a different distribution of disease pattern. 27 These differences in mortality rate may be a result of ethnicity or national differences between the populations in Brazil and Europe, such as the characteristics of CHD-PAH. [39][40][41] It is noteworthy that the proportion of CHD-PAH patients reported in our study is similar to Argentina, 42 but higher compared to Europe 37,38 and North America, 43,44 which could explain why we have a higher survival rate than in other studies at 1, 3, or 5 years of follow-up, even though we have fewer patients on double and triple combination therapy.
Patients with PAH-CHD had the best survival in the PAH group, which agrees with previous publications that have showed good long-term survival in these patients. 9,33,38,45 In a study published by Manes et al., the 5-year survival of patients with PAH-CHD was 91% compared with 63% in the contemporary group of idiopathic PAH patients in which the same treatment strategy was used. 46 In other series, a 3-year survival rates of 70% for idiopathic, heritable, or anorexigenic-associated PAH 47 and 56% for PAH-CTD 48 was described.
In the same line, a previous published study including incident cases from Brazil have shown that the third leading cause of PAH following idiopathic PAH and CTD-PAH was schistosomiasis (Sch-PAH). 28 According to the National Survey on the Prevalence of Schistosomiasis mansoni and Geohelminthiasis, 49 we can verify that there is a large discrepancy in the prevalence of schistosomiasis between different regions of Brazil. The southern region of Brazil is not an endemic region for schistosomiasis, and this may be an explanation for why no cases with this pathology were found in RESPHIRAR population.
Considering that there is no single variable that predicts outcomes in PAH patients, risk assessment in PAH patients should include a range of clinical, hemodynamic, and exercise parameters performed in a serial fashion to reflect a patient's course during the disease. 13,50 Risk stratification is an essential and relatively simple process to inform clinicians about prognosis, select treatment options, objectively monitor treatment response or disease progression, and optimize the timing of certain interventions such as lung transplantation. 20 The predominance of the intermediate risk group at baseline and the worse outcome as compared with the low-risk group has also been observed in the other registries studies. [15][16][17] Risk assessment is especially important in settings where clinical PAH experience is not available, as it could facilitate timely referral to a PAH center and/or lung transplantation. 50 In this context, REVEAL Lite 2.0 has clinical usefulness in screening patients because it can be used as a relatively quick and simple method for accurately identifying patients predicted to have a low risk of mortality. The REVEAL risk score calculator and its updated version (REVEAL 2.0) appeared accurate and well calibrated in validation cohorts, which confirms their generalizability. 6 Registries are important to characterize populations, assess the burden of diseases and describe practice patterns. In contrast to a prospective study, registries generally do not provide scheduled data entry or allow inclusion of patients only according to predefined datasets. 1,5 Patient registries collecting observational data can be of great value in the understanding of clinical problems. While clinical trials provide data in selected patient populations, registries better depict real-life practice. 5 Some strengths and limitations of the present study should be acknowledged. Among the study's strengths are the sample size, being a multicenter study with standardized, albeit retrospective, data collection, and comparable results. As limitations, first, the potential loss of patients to follow-up and the difficulty defining the time of diagnosis in prevalent patients. The study is prone to common standard limitations of a register-based descriptive study, including (1) lack of a standardized treatment protocol; (2) immortal time bias, which refers to a span of time in the observation or follow-up period of a cohort during which the outcome under study could not have occurred; and (3) case-wise deletion of patients due to missing data.
In conclusion, we found that the risk assessment strategy proposed by REVEAL 2.0 and REVEAL Lite 2.0 is valid for the prediction of long-term prognosis in PAH patients undergoing treatment in Brazil. Importantly, objective multivariable risk scores are better at predicting a patient's risk than clinical gestalt which is why such tools are essential in modern clinical practice.

AUTHOR CONTRIBUTIONS
All authors have participated in the conceptualization, writing and interpretation of the content and have approved the final version of this article.